In animals and humans, stress and corticosteroid excess is associated with changes in memory and hippocampal structure. A consistent finding during corticosteroid exposure is a decline in performance on declarative memory tasks. The human literature is quite limited. However, impairment in declarative memory and hippocampal atrophy, have been reported in patients with corticosteroid excess due to Cushing's disease, and, more recently by our group, in medically ill patients receiving prescription corticosteroid therapy. These have important implications to patients with mood disorders, as a subset of people with major depressive disorder and bipolar disorder have elevated cortisol levels. In animals, hippocampal changes secondary to corticosteroids can be attenuated with agents that modulate excitatory amino acids. Histological changes can be prevented and reversed with phenytoin, a glutamate release inhibitor, or an N-methyl-D-aspartate (NMDA) receptor antagonist. Our group has developed a research program using patients in medical settings receiving prescription corticosteroid (e.g., prednisone) therapy as a model system to explore the effects of cortisol elevations on the human brain. In prior studies, we have documented deficits in declarative memory, changes in N-acetyl aspartate (NAA, a marker of neuronal viability), and reduction in hippocampal volume during chronic exposure to prednisone. Lamotrigine is an antiseizure and bipolar disorder medication that decreases glutamate release through interactions with sodium and calcium channels. We conducted both open-label and placebo-controlled trials of lamotrigine in corticosteroid-treated patients finding statistically and clinically significant improvement in declarative memory. A larger and longer definitive trial is now proposed. We propose a randomized, double-blind, placebo-controlled pilot study of lamotrigine in 50 outpatients with asthma receiving chronic oral corticosteroid therapy. We hypothesize that the group receiving lamotrigine will show improvement in declarative memory relative to the placebo group. We will also assess NAA and glutamate using spectroscopy and hippocampal and amygdala volume using structural magnetic resonance imaging. We have assembled a research team with expertise in mood disorders, clinical trials, neuropsychology, asthma, statistics, hippocampal physiology, spectroscopy, and the neuroendocrine system to conduct the study. The findings will have implications for patients with major depressive disorder and the millions treated each year with prescription corticosteroids. PUBLIC HEALTH RELEVANCE: A large literature in animals suggests that stress hormones (corticosteroids) are associated with reversible and irreversible changes in the hippocampus, a brain structure that plays a critical role in learning and memory. In animal models, agents that inhibit the release of excitatory amino acids appear to block the effects of stress hormones on the hippocampus. In the proposed study, a randomized, controlled trial of lamotrigine, a medication that inhibits the release of excitatory amino acids, is proposed in a group of patients taking medically necessary prescription corticosteroids for asthma. The impact of lamotrigine on memory, mood, quality of life, structural imaging, and spectroscopy will be examined.